Systems and methods for treating a psychiatric disorder

ABSTRACT

Systems and methods for treating a subject with a psychiatric disorder are provided in which a therapy session is conducted. In the therapy session, each respective expression image in a plurality of expression images is sequentially displayed. Each expression image is independently associated with an expression. The successive display of images is construed as a tiled series of expression image subsets, each consisting of N expression images. Upon completion of the display of each respective subset, the user is challenged as to whether the first and the last images in the respective subset exhibit the same emotion. A score is determined for the respective subset based on whether the subject learned to respond correctly. The number of images in each subset is adjusted to a new number based on these scores. A treatment regimen is prescribed to the subject for the psychiatric disorder based at least in part on the scores.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to and is a continuation of U.S.patent application Ser. No. 15/513,490, filed Mar. 22, 2017, entitled“SYSTEMS AND METHODS FOR TREATING A PSYCHIATRIC DISORDER,” which in turnis a national stage application, filed under 35 U.S.C. § 371, of PCTApplication No. PCT/US2015/051791, filed Sep. 23, 2015, entitled“SYSTEMS AND METHODS FOR TREATING A PSYCHIATRIC DISORDER,” which claimspriority to U.S. Provisional Application No. 62/054,371, entitled“SYSTEMS AND METHODS FOR TREATING A PSYCHIATRIC DISORDER,” filed Sep.23, 2014, all of which are hereby incorporated by reference in theirentireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under 1K23MH099223-01A1awarded by The National Institute of Health. The government has certainrights in the invention.

TECHNICAL FIELD

The present invention relates generally to psychiatric disordertreatments. More particularly, the invention is directed to treatmentsrelating to affective disorders (AD).

BACKGROUND

There is an urgent need for more effective treatments for psychiatricdisorders characterized by negative affect (Affective Disorders or ADs),such as major depressive disorder (MDD), post-traumatic stress disorder(PTSD), and anxiety disorders. Such ADs are common, disabling andcostly. Indeed, an estimated 350 million people worldwide suffer fromdepression, which is the leading cause of disability in Americans ages15-44. Novel interventions are needed as available therapies precipitateremission in only one third of subjects.

SUMMARY

Psychiatric disorders, including affective disorders (ADs), can betreated by neurobehavioral therapies (NBTs) that stimulate the networkof brain regions implicated in these disorders. In particular, cognitiveemotional exercises can enhance cognitive control of emotionalinformation-processing that simultaneously activates brain regions(e.g., the dorsolateral PFC (DLPFC) and amygdala) that are impaired insuch ADs. Without being bound by any particular theory of operation ormechanism, it is believed that exercising the ability to manipulateemotional information in working memory by performing such cognitiveemotional exercises enhances cognitive control for emotional materialand emotion regulation, and has antidepressant effects.

In one aspect, provided herein is a computing system for the treatmentof a psychiatric disorder. The computing system includes one or moreprocessors, memory, and one or more programs. The one or more programsare stored in the memory and are configured to be executed by the one ormore processors to treat a subject in need of treatment of a psychiatricdisorder. The one or more programs include instructions for conducting atherapy session and prescribing a treatment regimen to the subject forthe psychiatric disorder. The therapy session comprises sequentiallydisplaying each respective expression image in a plurality of expressionimages for a predetermined amount of time. Each expression image in theplurality of expression images is images is (i) independently associatedwith a respective expression in a set of expressions and (ii) engineeredto display a predetermined intensity of the respective expression on anintensity scale that ranges from low intensity to high intensity of therespective expression. In other words, expression images are engineeredto display a certain intensity of the expression (e.g., level 1 includesexpression images with 90% intensity, level 2 includes expression imageswith 80% intensity, level 3 includes expression images with 70%intensity, level 4 includes expression images with 60% intensity, andlevel 5 includes expression images with 50% emotion intensity in theimages). This contributes to the difficulty of the task across levels.This is purposeful to increase engagement and learning throughout thesession.

Although each expression image is independently displayed a slidingwindow of the last N expression images is termed an “expression imagesubset.” As such, by the time all of the expression images have beendisplayed, a plurality of expression image subsets has necessarily beendisplayed. Accordingly, in the therapy session, responsive to completion(e.g. display) of the expression images in a respective expression imagesubset within the plurality of expression images, a response from thesubject to a query as to whether the first and the last expression imagein the respective expression image subset exhibits the same emotion isreceived. In other words, after each expression image subset isdisplayed, the subject is challenged as to whether the first and lastexpression image in the expression image subset connotes the sameexpression. Each respective expression image subset within the pluralityof expression images consists of N sequentially displayed expressionimages. The value N is a predetermined integer the value of which isdetermined by the stage in the therapy session the subject has achieved.In the therapy session, a score is determined for each respectiveexpression image subset within the plurality of expression image subsetsbased at least in part upon (a) the response to the query for therespective expression image subset, (b) the expression associated withthe first expression image in the respective expression image subset,and (c) the expression associated with the last expression image in therespective expression image subset. In this way a plurality of scores isdetermined. The therapy session continues by resetting the value of N toa new positive integer value based at least in part on the plurality ofscores. In some optional embodiments, the therapy session continues byprescribing a treatment regimen to the subject based at least in part onthe reset value of N or some other aspect of the above identifiedscoring process.

In some embodiments, the psychiatric disorder is an affective disorder(AD). In certain embodiments, the AD is major depressive disorder (MDD),bipolar disorder, post traumatic stress disorder (PTSD), general anxietydisorder, social phobia, obsessive compulsive disorder, treatmentresistant depression, or borderline personality disorder. In particularembodiments, the affective disorder is MDD.

In some embodiments, the sequentially displaying, receiving,determining, and resetting are repeated a plurality of times in thetherapy session. In certain embodiments, the sequentially displaying,receiving, determining, and resetting are repeated 10 to 20 times duringa therapy session.

In some embodiments, the value of N prior to the initial resetting isone, two, three, four, five, six, seven, eight, nine or ten. Inparticular embodiments, the value of N prior to the initial resetting istwo.

In some embodiments, there are ten to twenty respective expression imagesubsets. In particular embodiments, there are twenty respectiveexpression image subsets.

In some embodiments, the respective expression image subsets areoverlapping. In certain embodiments, the expression image subsetsoverlap by N−1 images with another respective image subset.

In some embodiments of the computing system, the set of expressionsinclude happy, worried, angry and sad. In some embodiments, there aretwo, three, four or five different expression images that areindependently associated with each expression in the set of expressions.

In some embodiments, the therapy session is repeated on a recurringbasis over the course of a number of weeks. In some embodiments, thetherapy session is repeated on a recurring basis over the course of anumber of weeks prior to prescribing a treatment regimen to the subject.In certain embodiments the therapy session is repeated two to ten timesover the course of a number of weeks prior to the prescribing.

In some embodiments, the treatment regimen is characterized by afrequency by which the therapy session is conducted as well as anabsolute number of times the therapy sessions are conducted.

In some embodiments, the treatment regimen is characterized by afrequency by which the therapy session is conducted as well as anabsolute number of times the therapy sessions are conducted andfurthermore is characterized by the use of a pharmaceutical composition.In some embodiments, the affective disorder is MDD and thepharmaceutical composition is a selective serotonin reuptake inhibitor(SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), acognitive enhancer, ketamine or ketamine derivative or combinationsthereof. In some embodiments, the affective disorder is post traumaticstress disorder (PTSD) and the pharmaceutical composition is an SSRI, anSNRI, a cognitive enhancer or combinations thereof. In some embodiments,the affective disorder is general anxiety disorder and thepharmaceutical composition is an SSRI, an SNRI, a cognitive enhancer,ketamine or a ketamine derivative or combinations thereof. In someembodiments, the affective disorder is social phobia and thepharmaceutical composition is an SSRI, an SNRI, a cognitive enhancer orcombinations thereof. In some embodiments, the affective disorder isobsessive compulsive disorder and the pharmaceutical composition is anSSRI, a cognitive enhancer or combinations thereof. In some embodiments,the affective disorder is borderline personality disorder and thepharmaceutical composition is an SSRI, an SNRI, ketamine or a ketaminederivative, a cognitive enhancer or combinations thereof.

In some embodiments, the treatment regimen is characterized by afrequency by therapy session the therapy session is conducted as well asan absolute number of times the therapy session is conducted andfurthermore is characterized by the use of a brain stimulationintervention. In certain embodiments, the brain stimulation interventionstimulates the dorsal lateral prefrontal cortex (DLPFC). In certainembodiments, the brain stimulation intervention is transcranial directcurrent stimulation.

In some embodiments, the treatment regimen is characterized by afrequency by which the therapy session is conducted as well as anabsolute number of times the therapy session is conducted andfurthermore is characterized by the use of a psychotherapy for anaffective disorder. In certain embodiments, the psychotherapy is anempirically supported psychotherapy for an affective disorder. Incertain embodiments, the psychotherapy is a cognitive behavioralpsychotherapy.

In some embodiments, the predetermined amount of time that respectiveimages are displayed is less than ten seconds. In some embodiments, thepredetermined amount of time that respective images are displayed isbetween 0.2 seconds and 10 seconds.

In some embodiments, each expression image in the plurality ofexpression images is grey scaled. In other embodiments, each expressionimage in the plurality of expression images is in color. In yet otherembodiments, the plurality of expression images includes color and greyscaled expression images.

In some embodiments, the prescribing comprises communicating the scoreto a remote server for evaluation by a prescribing clinician.

In some embodiments, the sequentially displaying comprises retrievingthe plurality of expression images from a database that stores theplurality of expression images. Such a database stores, for eachrespective expression image in the plurality of expression images, theemotion associated with the respective expression image.

In some embodiments, the plurality of scores is determined as the totalnumber of correct responses from the subject to the query as to whetherthe first and last expression in a respective expression image subset isthe same. In certain embodiments, the resetting of N is based at leastin part on the percentage of correct responses from the subject to thequery as compared to the total number of response. In some embodiments,N is reset to N+Y if the percentage of correct responses is greater thana first threshold percentage, N is reset to N−Y if the percentage ofcorrect responses is less than a second threshold percentage and N doesnot reset if the percentage of correct responses is between the firstand second threshold percentage. In some embodiments, Y is the value 1.In some embodiments, the value of Y is an integer value that isdetermined by the size of N. For instance, in one embodiment, if N isfive or less, Y is 1, whereas if N is six or greater, Y is 2.

In some embodiments an initial assessment of the subject is held priorto conducting the therapy session in order to select the appropriatetherapy session treatment protocol from among a plurality of therapysession treatment protocols. In certain embodiments, the initialassessment includes obtaining information regarding the cognitivefunctioning and/or the emotional functioning of the subject.

In some embodiments, the prescribing of the treatment regimen is furtherbased at least in part on the cognitive functioning and emotionalfunctioning of the subject after the training session. In someembodiments, the subject is assessed after conducting the therapy. Insuch embodiments, this assessment is used as the basis, at least inpart, for the prescribing a treatment regimen to the subject. Inparticular embodiments, the assessment is of the cognitive functionand/or emotional function of the subject.

In some embodiments, the subject is provided with a performanceevaluation based at least in part on the score determined for arespective expression image subset in the therapy session. In someembodiments, the subject is provided with a performance evaluation basedat least in part on the plurality of scores of a therapy session. Insome embodiments, the subject is provided with a performance evaluationbased at least in part on the plurality of scores of a plurality oftherapy sessions.

In some embodiments, the therapy session is repeated on a recurringbasis over the course of a number of weeks prior to prescribing atreatment regimen to the subject, and furthermore, the subject isintermittently evaluated for the presence of one or more symptoms of thepsychiatric disorder to be treated. In certain embodiments, thisintermittent evaluation for the presence of one or more symptoms of thepsychiatric disorder to be treated includes a patient healthquestionnaire (PHQ) check (e.g., PHQ-2, PHQ-9, PHQ-15, GAD-7, etc.).

The computing system of any one of claims 1-35, wherein at least oneexpression image in the plurality of expression images is not a facialexpression.

The computing system of any one of claims 1-35, wherein each expressionimage in the plurality of expression images is not a facial expression.

The computing system of any one of claims 1-35, wherein at least oneexpression image in the plurality of expression images is a facialexpression.

The computing system of any one of claims 1-35, wherein each expressionimage in the plurality of expression images is a facial expression.

In some embodiments, the predetermined intensity of the respectiveexpression on the intensity scale of respective displayed expressionimages increases from the low intensity to the high intensity across thetherapy session. In some embodiments, the therapy session reduces thedepression symptoms of the subject by at least 10%, at least 20%, atleast 30%, at least 40%, at least 50%, at least 60%, or at least 70%.

In some embodiments, at least one expression image in the plurality ofexpression images is not a facial expression. In some embodiments, eachexpression image in the plurality of expression images is not a facialexpression. In some embodiments at least one expression image in theplurality of expression images is a facial expression. In someembodiments each expression image in the plurality of expression imagesis a facial expression.

BRIEF DESCRIPTION OF THE DRAWINGS

For a better understanding of the aforementioned implementations of theinvention as well as additional implementations thereof, referenceshould be made to the Description of Implementations below, inconjunction with the following drawings in which like reference numeralsrefer to corresponding parts throughout the figures.

FIG. 1 is a block diagram of an electronic network for providing atreatment for a subject in need of treatment of a psychiatric disorder,according to some embodiments.

FIG. 2 is a block diagram of the subject device memory shown in FIG. 1,according to some embodiments.

FIGS. 3A-3C are flow charts of a method for treating a psychiatricdisorder, according to some embodiments.

FIG. 4A is a graph showing the change in depression severity over timebetween a group having MDD undergoing an EFMT therapy session and a CTcontrol group. As shown in the graph, the EFMT group demonstrated asignificant reduction (from 21.55 to 10.91; p<0.001, d=2.67) that wasgreater than the CT group (from 19.80 to 14.10; p=0.01, d=1.08). Thedifference between groups in change in MDD symptoms over time(EFMT=−10.64; CT=−5.7) was large: d=0.82.

FIG. 4B is a graph showing the change in negative affective bias inshort-term memory over time between a group having MDD undergoing anEFMT therapy session and a CT control group. As shown in the graph, EFMTparticipants demonstrated a significant reduction in short-term memoryfor negative self-referential information (proportion of negativeself-descriptors accurately recalled after a delay) from 0.1852 to0.1697 (p=0.037, d=−0.79), whereas the CT group showed a small andnon-significant increase from 0.1845 to 0.1885 (p=0.535, d=0.27). Thebetween-groups difference in change was medium-sized: d=0.60.

Reference will now be made in detail to implementations, examples ofwhich are illustrated in the accompanying drawings. In the followingdetailed description, numerous specific details are set forth in orderto provide a thorough understanding of the present invention. However,it will be apparent to one of ordinary skill in the art that the presentinvention may be practiced without these specific details.

DESCRIPTION OF IMPLEMENTATIONS

The implementations described herein provide various technical solutionsto improve the health of human subjects having a psychiatric disorder byproviding a treatment for a psychiatric disorder. Details ofimplementations are now described in relation to the Figures.

FIG. 1 is a diagrammatic view of an electronic network 100 for thetreatment of a psychiatric disorder in accordance with some embodiments.The network 100 comprises a series of points or nodes interconnected bycommunication paths. The network 100 may interconnect with othernetworks, may contain subnetworks, and may be embodied by way of a localarea network (LAN), a metropolitan area network (MAN), a wide areanetwork (WAN), or a global network (the Internet). In addition, thenetwork 100 may be characterized by the type of protocols used on it,such as WAP (Wireless Application Protocol), TCP/IP (TransmissionControl Protocol/Internet Protocol), NetBEUI (NetBIOS Extended UserInterface), or IPX/SPX (Internetwork Packet Exchange/Sequenced PacketExchange). Additionally, the network 100 may be characterized by whetherit carries voice, data, or both kinds of signals; by who can use thenetwork 100 (whether it is public or private); and by the usual natureof its connections (e.g. dial-up, dedicated, switched, non-switched, orvirtual connections).

The network 100 connects a plurality of subject devices 110 to at leastone psychiatric disorder treatment server 102. This connection is madevia a communication or electronic network 106 that may comprise anIntranet, wireless network, cellular data network or preferably theInternet. The connection is made via communication links 108, which may,for example, be coaxial cable, copper wire (including, but not limitedto, PSTN, ISDN, and DSL), optical fiber, wireless, microwave, orsatellite links. Communication between the devices and serverspreferably occurs via Internet protocol (IP) or an optionally securesynchronization protocol, but may alternatively occur via electronicmail (email).

The psychiatric disorder treatment server 102 is shown in FIG. 1, and isdescribed below as being distinct from the subject devices 110. Thepsychiatric disorder treatment server 102 comprises at least one dataprocessor or central processing unit (CPU) 212, a server memory 220,(optional) user interface devices 218, a communications interfacecircuit 216, and at least one bus 214 that interconnects these elements.The server memory 220 includes an operating system 222 that storesinstructions for communicating, processing data, accessing data, storingdata, searching data, etc. The server memory 220 also includes remoteaccess module 224 and an expression image library (database) 226. Insome embodiments, the remote access module 224 is used for communicating(transmitting and receiving) data between the psychiatric disordertreatment server 102 and the communication network 106. In someembodiments, the expression image database 226 is used to storeexpression images that can be used by one or more programs of thecomputing system provided herein (e.g., programs for conducting atherapy session).

In certain embodiments, the server memory 220 further includes a subjectdatabase 228 preferably containing a plurality of subject profiles 230-1to 230-Z. In some embodiments, each subject profile 230-1 to 230-Zcontains subject information 232, such as, but not limited to,performance scores of the therapy sessions described herein, pre andpost therapy session assessments, and/or therapy session histories. Incertain embodiments, the subject profile 230 further includes subjectcontact details, information concerning the subject's medical history,the subject's medical insurance details, etc. In some embodiments, thesubject database 228 also comprises information regarding psychiatricdisorder treatment plans such as, but not limited to, the frequency ofconducting therapy sessions describe herein, the absolute number oftimes that the therapy sessions are conducted, and/or anypharmaceuticals prescribed or other treatments (e.g., medication andother psychotherapies that target the brain regions and neural networksrelated to the psychiatric disorder being treated) administeredconcurrently with the treatments provided herein.

In some embodiments, a subject device 110 is a device used by a subjectin need of treatment of a psychiatric disorder as described herein. Thesubject device 110 accesses the communication network 106 via remoteclient computing devices, such as desktop computers, laptop computers,notebook computers, handheld computers, tablet computers, smart phones,or the like. In some embodiments, the subject device 110 includes a dataprocessor or central processing unit (CPU), a user interface device,communications interface circuits, and buses, similar to those describedin relation to the psychiatric disorder treatment server 102. In someembodiments, the subject device 110 includes a display 121 fordisplaying expression images as described below. The subject device 110also includes memories 120, described below. Memories 220 and 120 mayinclude both volatile memory, such as random access memory (RAM), andnon-volatile memory, such as a hard-disk or flash memory.

FIG. 2 is a block diagram of a subject device memory 120 shown in FIG.1, according to some embodiments. The subject device memory 120 includesan operating system 122 and remote access module 124 compatible with theremote access module 224 (FIG. 1) in the server memory 220 (FIG. 1).

In some embodiments, the subject device memory 120 includes a therapysession module 126. The therapy session module 126 includes instructionsfor conducting a therapy program, as detailed below. In someembodiments, the therapy session module 126 comprises one or moremodules for conducting a therapy session. For instance, in someembodiments, the therapy session module 126 included in the subjectdevice memory 120 comprises a display module 128, a receiving module130, a determination module 132, and a resetting module 134.

In some embodiments, the subject memory device memory 120 includes aprescribing program 136, wherein the prescribing program 136 containsinstructions to prescribe a treatment regimen to the subject undergoingthe treatment described herein. In some embodiments, the prescribing isbased at least in part on results generated by the therapy sessionprogram 126 (e.g., the reset value of N, as discussed in detail below).

In some embodiments, the subject device memory 120 also comprises asubject database 138 that stores data relating to the subject using thesubject device 110. In some embodiments, the subject database 138 storesdata relating to user subject's performance scores for a therapy sessionor plurality of therapy sessions as described herein, pre and posttherapy session assessments, and/or therapy session histories. In someembodiments, the subject database 138 also stores data relating to thesubject's psychiatric disorder treatment plan such as, but not limitedto, the frequency of conducting a therapy session describe herein, theabsolute number of times that therapy sessions are conducted, and/or anypharmaceuticals prescribed or other treatments (e.g., medication andother psychotherapies that target the brain regions and neural networksrelated to the psychiatric disorder being treated) administeredconcurrently with the treatments provided herein.

In some embodiments, the subject device memory 120 also comprises anexpression image database 140. In certain embodiments, the expressionimage database comprises expression images that are used in the therapysession of the computing system as described below.

It should be noted that the various databases described above have theirdata organized in a manner so that their contents can easily beaccessed, managed, and updated. The databases may, for example, compriseflat-file databases (a database that takes the form of a table, whereonly one table can be used for each database), relational databases (atabular database in which data is defined so that it can be reorganizedand accessed in a number of different ways), or object-orienteddatabases (a database that is congruent, with the data defined in objectclasses and subclasses). The databases may be hosted on a single serveror distributed over multiple servers. In some embodiments, there is anexpression image database 226 but no expression image database 140.

FIGS. 3A-C are flow charts that illustrate the method 300 for thetreatment of a psychiatric disease, according to some embodiments of thesubject computing system. In some embodiments, the method is carried outby one or more programs of the subject computer system described herein.

In some embodiments, the method is for the treatment of an affectivedisorder (AD). As used herein, an “affective disorder” refers to apsychological disorders characterized by abnormalities of emotionalstate (i.e., a mood disorder). Examples of affective disorders include,but are not limited to: attention-deficit hyperactivity disorder,bipolar disorder, body dysmorphic disorder, bulimia nervosa and othereating disorders, cataplexyy, dysthymia, general anxiety disorder,hypersexuality, irritable bowel syndrome impulse-control disorders,kleptomania, migraine, major depressive disorder, narcolepsy,obsessive-compulsive disorder, oppositional-defiant disorder, panicdisorder, posttraumatic stress disorder, premenstrual dysphoricdisorder, treatment resistant depression, and social anxiety disorder.In certain embodiments, the subject systems and methods described hereinare for the treatment of an affective disorder chosen from majordepressive disorder (MDD), post traumatic stress disorder (PTSD),general anxiety disorder, social phobia, obsessive compulsive disorder,treatment resistant depression and borderline personality disorder. Inparticular embodiments, the subject system and methods described hereinare for the treatment of MDD.

In some embodiments, the subject method comprises A) conducting atherapy session 302-326 and B) prescribing a treatment regimen 334 tothe subject for the psychiatric disorder. The conducting the therapysession includes sequentially displaying (304) each respectiveexpression image in a plurality of expression images for a predeterminedamount of time, where each expression image in the plurality ofexpression images is independently associated with an expression in aset of expressions. This sequential display of expression images can bethought of as the sequential display of expression image subsets in aplurality of expression image subsets, where each expression imagesubset consists of the last N displayed expression image subsets. Forinstance, in some embodiments, the expression image subsets are tiledwith respect to each other, such that they each overlap with atemporally neighboring expression image by one expression image.

In some embodiments, the set of expressions invoked by the plurality ofexpression images comprises four or more different expressions (e.g.,happy, worried, angry and sad) (306). In some embodiments, thepredetermined amount of time a particular expression image is displayedis random and independent of the amount of time any other image isdisplayed (308). In some embodiments, the amount of time between thedisplay of any two consecutive expression images is random andindependent of the amount of time between the display of any two otherconsecutive images (310).

In a therapy session, the subject is queried at the completion of eachrespective expression image subset within the plurality of expressionimages as to whether the emotion of the first and last expression imagein the respective image subset is the same (312). For instance, the userpresses a first key (e.g., “1”) if the expressions are the same and asecond key (e.g., “2”) if the expressions are different. Because therespective expression image subsets are temporarily tiled, this equatesin some embodiments to querying the subject after each expression imageonce the first expression image subset has been displayed. As such,responsive to completion of each respective expression image subset, aresponse from the subject to a query as to whether the first and thelast expression image in the respective expression image subset exhibitsthe same emotion is received. In such embodiments, each respectiveexpression image subset within the plurality of expression imagesconsists of N sequentially displayed expression images, where N is apredetermined integer (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or greater). Insome embodiments, the respective expression image subsets areoverlapping, where each subset (temporally) overlaps by N−1 images withanother respective image subset, where N is the number of expressionimages in each respective image subset. In some embodiments, therespective expression image subsets are overlapping, where each subset(temporally) overlaps by N−2 images with another respective imagesubset. In some embodiments, the respective expression image subsets areoverlapping, where each subset (temporally) overlaps by N−3 images withanother respective image subset. In some embodiments, the respectiveexpression image subsets are overlapping, where each subset (temporally)overlaps by N−Y images with another respective image subset, where N isthe number of images in each respective image subset and Y is an integerless than N.

In some embodiments, there are ten to twenty respective expression imagesubsets in the plurality of expression images (316). In someembodiments, there are between three and one hundred respectiveexpression image subsets in the plurality of expression images. In someembodiments, there are between three to fifty respective expressionimage subsets in the plurality of expression images. In someembodiments, there are between three to thirty respective expressionimage subsets in the plurality of expression images.

The therapy session continues with the determination of a score for eachrespective expression image subset within the plurality of expressionimages based at least in part upon (a) the response to the query for therespective expression image subset, (b) the expression associated withthe first expression image in the respective expression image subset,and (c) the expression associated with the last expression image in therespective expression image subset, thereby determining a plurality ofscores (318). In some embodiments, the plurality of scores is determinedas the total number of correct responses by the subject to the query(320).

The therapy session continues by resetting the value of N to a newpositive integer value based at least in part on the plurality of scores(322). In some embodiments, resetting of the positive integer N is basedat least in part on the percentage of correct responses from the subjectto the query as compared to the total number of response (324). In someembodiments, N is reset to N+Q if the percentage of correct responses isgreater than a first threshold percentage, is reset to N−Q if thepercentage of correct responses is less than a second thresholdpercentage and does not reset if the percentage of correct responses isbetween the first and second threshold percentage. Typically, Q if thevalue “1”, though other values are possible (e.g., 2, 3, 4, or any valueless than N).

In some embodiments, a treatment regimen is prescribed based at least inpart on the reset value of N (334).

Now that an overview of a therapy session has been detailed, somespecific embodiments will be described. In some embodiments, a therapysession (e.g., as disclosed in steps 302-326) comprises a first step of:i) sequentially displaying 304 each respective expression image in aplurality of expression images for a predetermined amount of time, whereeach expression image in the plurality of expression images isindependently associated with an expression in a set of expressions. Incertain embodiments of the computing system provided herein, thesequentially displaying is performed according to instructions includedin a display module 128 stored in the subject device memory 120 of asubject device 110.

In some embodiments, the sequentially displaying comprises retrieving aplurality of expression images from a database that stores expressionimages (e.g., an expression image database 140 and 226). In someembodiments, the expression image database further stores the emotionassociated with each expression image stored in the database. In certainembodiments, the database that stores expression images is included inthe server memory 220 of the psychiatric disorder treatment server 102.In other embodiments, the database that stores expression images islocated in the subject device memory 120 of the subject device 110.

In some embodiments, after the retrieval of a plurality of expressionimages from the expression image database 140 or 226, the images aresequentially displayed to the subject on a display 121 of the subjectdevice 110. In certain embodiments, the predetermined amount of timethat each particular expression image in the plurality of expressionimages is displayed is between 0.1 and 5.0 seconds. In certainembodiments, the predetermined amount of time that each particularexpression image in the plurality of expression images is displayed isbetween 0.5 and 3.5 seconds. In certain embodiments, all of theexpression images are sequentially displayed for the same predeterminedamount of time. In certain embodiments, each expression image in theplurality is displayed for a predetermined amount of time that is randomand independent of the amount of time any other image is displayed(308). In some embodiments, the predetermined amount of time that aparticular expression image is displayed is randomly chosen from a setof two to ten predetermined lengths of time. In some embodiments, theamount of time between the display of two consecutive images is between0.1 and 5.0 seconds. In certain embodiments, the amount of time betweenthe display of two consecutive images is between 0.75 and 3.5 seconds.In certain embodiments, the amount of time between the display of twoconsecutive images is the same for all consecutive images sequentiallydisplayed. In other embodiments, the amount of time between the displayof any two consecutive images is random and independent of the amount oftime between the display of any two other consecutive images 310. Insome embodiments, the amount of time between the display of twoconsecutive images is randomly chosen from a set of two to tendetermined lengths of time.

In some embodiments, the expression images comprise images of humanfacial expressions. Any image of a human facial expression can be usedin the subject systems and methods provided herein. The expressionimages can depict male and/or female, adult and/or children human facialexpression and facial expressions of humans of the same or differentages and ethnicities. In certain embodiments, the expression images ofthe plurality of expression images are grey scaled. In otherembodiments, the expression images of the plurality of expression imagesare in color. In yet other embodiments, the expression images of theplurality of expression images are a combination of grey scaled andcolor images. In some embodiments, the expression images arephotographs. In some embodiments, the expression images areillustrations. In certain embodiments, the expression images areanimated expression images. In some embodiments, expression images areengineered to display a certain intensity of the expression (e.g., level1 includes expression images with 90% intensity, level 2 includesexpression images with 80% intensity, level 3 includes expression imageswith 70% intensity, level 4 includes expression images with 60%intensity, and level 5 includes expression images with 50% emotionintensity in the images). This contributes to the difficulty of the taskacross levels. This is purposeful to increase engagement and learningthroughout the session.

In some embodiments, the expression images are associated with anexpression in a set of expressions. In some embodiments, the set ofexpressions comprises two, three, four, five, six, seven, eight, nine,or ten different expressions. In some embodiments the set of expressionsconsists of two, three, four, five, six, seven, eight, nine, ten or morethan ten expression selected from the set of expressions {agonized,angry, annoyed, ashamed, bashful, black, bleak, blissful, blithe,bloodthirsty, brooding, cautious, chagrined, choleric, confident,confused, contemptuous, coy, crestfallen, curious, deadpan, dejected,despondent, discouraged, displeased, doleful, dour, downcast, dreamy,delighted, dumbfounded, ecstatic, expressionless, furtive, glazed,gloomy, glowering, glowing, grim, grave, haunted, hot-tempered,frightened, hopeless, hostile, impassive, indignant, inexpressive,intimidating, irate, jeering, languid, leering, mischievous, mocking,pained, pallid, peeved, petulant, pleading, preoccupied, pouting,quizzical, questioning, radiant, resentful, sad, sanguine, sardonic,scornful, scowling, searching, serious, shamefaced, sneering, somber,sour, straight-faced, sullen, sulky, surprised, suspicious, stern,stolid, taunting, tense, threatening, vengeful, wan, wary, wistful,withering, woeful, worried, wrathful, wry, and yearning}. In someembodiments the expression images are facial expressions of a human.However, the present disclosure is not so limiting. In some embodimentsare any image that induces amygdala activation (images that areemotionally salient or evocative).

In certain embodiments, the set of expression comprises four differentexpressions. In particular embodiments, the set of expressions is{happy, worried, angry, and sad} (306). In certain embodiments, theplurality of expression images consists of one image associated with aparticular expression in the set of expressions. In other embodiments,the plurality of images consists of two, three, four, five, six seven,eight, nine or ten or more different expression images associated witheach expression in the set of expressions.

In some embodiments, the conducting a therapy session 302-326 comprisesthe step of, responsive to completion of each respective expressionimage subset within the plurality of expression images, receiving 312 aresponse from the subject to a query as to whether the first and thelast expression image in the respective expression image subset exhibitsthe same emotion, where each respective expression image subset withinthe plurality of expression images consists of N sequentially displayedexpression images, and where N is a predetermined integer. In certainembodiments of the computing system provided herein, the receiving isperformed according to instructions included in a receiving module 128stored in the subject device memory 120 of a subject device 110.

In some embodiments, N is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In someembodiments, the respective expression image subsets arenon-overlapping, meaning that there are no expression images commonbetween respective expression image subsets. In certain embodiments, therespective expression subsets are overlapping. In certain embodiments,each respective expression subset consists of N images and N−1 of theseimages are found in another expression subset in the plurality ofexpression subsets.

In particular embodiments, the respective expression image subsetsoverlap by N−1 expression images 314. As such, consecutive expressionimage subsets in these embodiments differ by one expression image. Forexample, for a plurality of images that are sequentially displayed as:

A, B, C, D, E, F, G, H, I, J, K, L, M,

where each expression image subset contains N=4 sequentially displayedexpression images, the expression image subsets that overlap by N−1expression images are 1) A, B, C, D; 2) B, C, D, E; 3) C, D, E, F; 4) D,E, F, G, etc. . . .

As such, for expression image subsets that overlap by N−1, thecompletion of the display of an expression image subset after thecompletion of the first expression image subset occurs after the displayof each image after the first N images.

In certain embodiments, there are ten to twenty respective expressionimage subsets in the plurality of expression images that aresequentially displayed 316. In other words, there are ten to twentyresponses received from the subject in such embodiments. In particularembodiments, there are twenty respective expression image subsets in theplurality of expression images that are sequentially displayed 316.

In some embodiments, the conducting a therapy session 302-326 comprisesthe step of determining a score 318 for each respective expression imagesubset within the plurality of expression images based at least in partupon (a) the response to the query for the respective expression imagesubset, (b) the expression associated with the first expression image inthe respective expression image subset, and (c) the expressionassociated with the last expression image in the respective expressionimage subset, thereby determining a plurality of scores. In certainembodiments of the computing system provided herein, the determining isperformed according to instructions included in a determining module 132stored in the subject device memory 120 of a subject device 110. In someembodiments, the plurality of scores is determined as the total numberof correct responses by the subject to the query as to whether the firstand last expression image in a respective expression image subsetexhibits the same emotion 320.

In some embodiments, the conducting a therapy session 302-326 comprisesthe step of resetting (322) the value of N to a new positive integervalue based at least in part on the plurality of scores. In certainembodiments of the computing system provided herein, resetting 322 isperformed according to instructions included in a resetting module 134stored in the subject device memory 120 of a subject device 110.

In certain embodiments, the resetting of N is based at least in part onthe percentage of correct responses by the subject to the query ascompared to the total number of responses 324. In some embodiments, N isreset to N+X if the percentage of correct responses is greater than aset threshold percentage, wherein X is 1, 2, 3, 4, or 5. In certainembodiments, N is reset to N+1 if the percentage of correct responses isgreater than 80%-90%. In certain embodiments, N is reset to N+1 if thepercentage of correct responses is greater than 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, or 90%. In some embodiments, N is reset to N−Xif the percentage of correct responses is less than a set thresholdpercentage, wherein X is 1, 2, 3, 4, or 5. In some embodiments, N isreset to N−1 if the percentage of correct responses is less than 55-70%.In some embodiments, N is reset to N−1 if the percentage of correctresponses is less than 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%,or 70%. In some embodiments, N is not reset if the percentage of correctresponses is within a particular range of percentages. In certainembodiments, N is reset to N+1 if the percentage of correct responses isgreater than a first threshold percentage, N is reset to N−1 if thepercentage of correct responses is less than a second thresholdpercentage and N does not reset if the percentage of correct responsesis between the first and second threshold percentage 326. In certainembodiments, the first threshold percentage is about 85% and the secondthreshold percentage is about 65%.

In some embodiments, the therapy session comprises repeating thedisplaying i) receiving ii), determining iii), and resetting iv) aplurality of times (328). In particular embodiments, the repeatingoccurs prior to prescribing a treatment regimen (334). In certainembodiments, the repeating is on a recurring basis over the course of aperiod of time prior to prescribing a treatment regimen. In certainembodiments, the repeating is on a recurring basis over the course of anumber of weeks prior to prescribing a treatment regimen.

In some embodiments, the repeating is on a recurring basis over a periodof time prior to prescribing a treatment regimen, the subject undergoesthe therapy session, and is also intermittently evaluated for one ormore symptoms of the psychiatric disorder being treated. In certainembodiments, the computing system described herein includes one or moreprograms that include instructions for intermittently evaluating thesubject for one or more symptoms of the psychiatric disorder beingtreated. In particular embodiments, the instructions compriseinstructions for performing a patient health questionnaire (PHQ) check(e.g., PH-QA, PHQ-2, PHQ-8, PHQ-9, PHQ-15, GAD-2, GAD-7, etc.). See,e.g., Kroenke et al., General Hospital Psychiatry 32: 345-359 (2010),which is hereby incorporated by reference. For instance, in certainembodiments, the subject undergoing the therapy session is alsoevaluated for cognitive biases and/or neurocognition intermittently.Tests for cognitive biases include, for example, self-referentialinformation processing (SRIP) task, cognitive style questionnaires (CSQ)and ruminative responses scale (RRS). Tests for neurocognition includetests for working memory, for example, tests that test digit-spanforward and back, and letter number sequencing. In certain embodiments,the computing system described herein also includes one or more programsthat include instruction for intermittently evaluating the subject'scognitive biases and/or neurocognition.

As used herein, a “block” with respect to the therapy session describedherein refers to one iteration (instance) of the steps of displaying i)receiving ii), determining iii), and resetting iv). In some embodiments,the therapy session comprises 3 to 200 blocks. In certain embodiments,the therapy session comprises 3 to 15 blocks. In certain embodiments,the therapy session comprises 3 to 15 blocks that occur prior toprescribing a treatment regimen 334.

In some embodiments, the method provided herein comprises the step ofprescribing a treatment regimen to the subject based at least in part onthe reset value of N (334). In some embodiments, the prescribingcomprises communicating the score to a remote server (e.g., apsychiatric disorder treatment server 102) for evaluation by aprescribing clinician 336. In some embodiments, the communicating isperformed by the prescribing program 136, located in the subject devicememory 120 of the subject device 110 described herein. In certainembodiments, the treatment regimen comprises a frequency of conductingthe therapy session and an absolute number of times to conduct thetherapy session 338. In certain embodiments the therapy sessioncomprises three or more blocks, sequential blocks are grouped intolevels, where each level comprises an equal number of blocks. Forexample, in certain embodiments, the therapy session comprisesperforming 15 blocks and 5 levels, where each of the 5 levels consistsof 3 blocks. In certain embodiments, the prescribing a treatment regimenis based at least in part on the average of the reset value of N in thelast block of every level.

In some embodiments, the treatment regimen comprises a frequency ofconducting the therapy session an absolute number of times to conductthe therapy session and the use of a pharmaceutical composition 340, abrain stimulation intervention 342, and/or an empirically supportedpsychotherapy 344. Without being bound by any particular theory ofoperation, it is believed that combining different approaches (e.g.,medications, brain stimulation interventions and psychotherapies) thattarget overlapping neural system provides additive effects in thetreatment of affective disorders. In certain embodiments, the treatmentregimen is characterized by a frequency of conducting the therapysession (e.g., once a week, twice a week, three times a week, daily,every other week), an absolute number of times to conduct the therapysession (e.g., 10 times, 20 times, 30 times), and the use of apharmaceutical composition 340. In certain embodiments, the treatmentregimen is characterized by frequency of conducting the therapy session(e.g., once a week, twice a week, three times a week, daily, every otherweek), an absolute number of times to conduct the therapy session (e.g.,10 times, 20 times, 30 times), and the use of a brain stimulationintervention 342. In certain embodiments, the treatment regimen ischaracterized by frequency of conducting the therapy session (e.g., oncea week, twice a week, three times a week, daily, every other week), anabsolute number of times to conduct the therapy session (e.g., 10 times,20 times, 30 times), and the use of an empirically supportedpsychotherapy 344. In other embodiments, the treatment regimen ischaracterized by frequency of conducting the therapy session (e.g., oncea week, twice a week, three times a week, daily, every other week), anabsolute number of times to conduct the therapy session (e.g., 10 times,20 times, 30 times), the use of a pharmaceutical composition 340 and theuse of a brain intervention mechanism 342. In other embodiments, thetreatment regimen is characterized by frequency of conducting thetherapy session (e.g., once a week, twice a week, three times a week,daily, every other week), an absolute number of times to conduct thetherapy session (e.g., 10 times, 20 times, 30 times), the use of apharmaceutical composition 340 and the use of an empirically supportedpsychotherapy 344. In yet other embodiments, the treatment regimen ischaracterized by frequency of conducting the therapy session (e.g., oncea week, twice a week, three times a week, daily, every other week), anabsolute number of times to conduct the therapy session (e.g., 10 times,20 times, 30 times), the use of a brain intervention mechanism 342 andthe use of an empirically supported psychotherapy 344. In yet otherembodiments, the treatment regimen is characterized by frequency ofconducting the therapy session (e.g., once a week, twice a week, threetimes a week, daily, every other week), an absolute number of times toconduct the therapy session (e.g., 10 times, 20 times, 30 times), theuse of a pharmaceutical composition 340, the use of a brain interventionmechanism 342, and the use of an empirically supported psychotherapy344.

In certain embodiments, the treatment regimen is characterized byfrequency of conducting the therapy session (e.g., once a week, twice aweek, three times a week, daily, every other week), an absolute numberof times to conduct the therapy session (e.g., 10 times, 20 times, 30times), and the use of a pharmaceutical composition (340). Thepharmaceutical composition prescribed will depend on the psychiatricdisorder being treated. Pharmaceutical compositions known for treatingan affective disorder include, but are not limited to, selectiveserotonin reuptake inhibitors (SSRI, e.g., fluoxetine, sertraline,paroxetine, citalopram, escitalopram, dapoxetine, seproxetine,mesembrin, and zimelidine), serotonin norepinephrine reuptake inhibitors(SNRI, e.g., venlafaxine, desvenlafaxine, duloxetine, milnacipran,levomilnacipran, and sibutramine), cognitive enhancers (e.g., adderall,ritalin, dexadrin, modafinil), ketamine and ketamine derivatives,atypical antipsychotics, benzodiazepines, bupropion, amotrigine,lithium, monoamine oxidase inhibitors, tricyclic antidepressants,valproic acid, nefazodone, trazodone, and pramipexole. For suitabledosaging and selection of some such compounds, see U.S. Pat. No.8,785,500, entitled “Intranasal Administration of Ketamine to TreatDepression,” which is hereby incorporated by reference herein in itsentirety for such purpose.

In certain embodiments, the psychiatric disorder is MDD and thepharmaceutical composition is an SSRI, an SNRI, a cognitive enhancer,ketamine or a ketamine derivative, an atypical antipsychotic, abenzodiazepine, bupropion, amotrigine, lithium, a monoamine oxidaseinhibitor, a tricyclic antidepressant, valproic acid, nefazodone,trazodone, pramipexole or combinations thereof. In certain embodiments,the psychiatric disorder is post traumatic stress disorder (PTSD) andthe pharmaceutical composition is an SSRI, an SNRI, a cognitiveenhancer, ketamine or a ketamine derivative or combinations thereof. Inother embodiments, the psychiatric disorder is general anxiety disorderand the pharmaceutical composition is an SSRI, an SNRI, a cognitiveenhancer or combinations thereof.

In some embodiments, the psychiatric disorder is social phobia and thepharmaceutical composition is an SSRI, an SNRI, a cognitive enhancer orcombinations thereof. In other embodiments, the psychiatric disorder isobsessive compulsive disorder and the pharmaceutical composition is anSSRI, a cognitive enhancer or combinations thereof. In some embodiments,the psychiatric disorder is borderline personality disorder and thepharmaceutical composition is an SSRI, an SNRI, ketamine or ketaminederivative, a cognitive enhancer or combinations thereof.

In some embodiments, the treatment regimen is characterized by afrequency of conducting the therapy session, an absolute number of timesto conduct the therapy session, and the use of a brain stimulationintervention 342. In some embodiments the brain intervention targets theamygdala and dorsolateral prefrontal cortical (DLPFC) brain regions.Without being bound by any particular theory of operation, it isbelieved that neural circuitry abnormalities within these regions causethe subsequent biased and prolong processing of negative emotionalinformation associated with some affective disorders (e.g., MDD). Insome embodiments, the brain target intervention activates the amygdalaand DLPFC regions. In some embodiments the brain target intervention istranscranial direct current stimulation, deep brain stimulation and/ortranscranial magnetic stimulation (TMS).

In some embodiments, where the therapy session comprises repeating thedisplaying i) receiving ii), determining iii), and resetting iv) aplurality of times (328) prior to prescribing a treatment regimen, oneor more brain target interventions described herein can be administeredconcurrently during the therapy session or prior to conducting a therapysession. Further, in some embodiments, one or more of the pharmaceuticalcompositions disclosed herein may be administered prior to conductingthe therapy session or after the therapy session, as part of a treatmentregimen.

In certain embodiments, the treatment regimen is characterized byfrequency of conducting the therapy session (e.g., once a week, twice aweek, three times a week, daily, every other week), an absolute numberof times to conduct the therapy session (e.g., 10 times, 20 times, 30times), and the use of an empirically supported psychotherapy 344. Incertain embodiments, the empirically supported psychotherapy is acognitive-behavioral psychotherapy.

In certain embodiments, the computing system described herein includesone or more programs that include instructions for conducting an initialassessment of the subject prior to conducting the therapy in order toselect the therapy session from among a plurality of therapy sessionprotocols 302. In certain embodiments, the initial assessment comprisesassessing the user subject for one or more symptoms of the affectivedisorder being treated. In particular embodiments, the instructionscomprise instructions for performing a patient health questionnairecheck (e.g., PHQ-2, PHQ-9, PHQ-15, GAD-7, etc.). In certain embodiments,the subject is also initially assessed for cognitive biases,neurocognition, and/or emotional function intermittently. In certainembodiments, the computing system described herein also includes one ormore programs that include instruction for intermittently evaluating thesubject's cognitive biases and/or neurocognition.

In some embodiments, a performance evaluation is provided to the userafter the completion of a block, a plurality of blocks or a therapysession. In certain embodiments, one or more programs of the computingsystem provided herein include instructions for generating a performanceevaluation. In some embodiments, the performance evaluation is based onthe reset value of N at the completion of a block, a plurality ofblocks, or a therapy session. In some embodiments wherein the therapysession is carried out in levels of blocks, the performance evaluationis based on the average of the reset values of N of the last block atevery level.

EXAMPLES Example 1. Cognitive-Emotional Training as an Intervention forMajor Depressive Disorder

There is an urgent need for more effective treatments for affectivedisorders, including, for example, major depressive disorder (MDD). Asunderstanding of the cognitive and affective neuroscience underlyingpsychiatric disorders expands, so do opportunities to developinterventions that capitalize on the capacity for brain plasticity.Cognitive training is one such strategy. A novel cognitive-emotionaltraining exercise designed to enhance cognitive control for emotionalinformation-processing and targeting components of the neural networksthat have been implicated in MDD is shown below.

E-1-1. Methods and Materials.

E-1-1-1 Participants.

Twenty-one currently un-medicated MDD participants were recruitedthrough advertisements for depression research studies. Participantsbetween ages 18-55 were diagnosed by trained masters and doctoral-levelclinicians using the Structured Clinical Interview for DSM-IV-TR Axis IDisorders (SCID). Participants met criteria for MDD diagnosis and couldhave other Axis I diagnoses (excluding psychotic disorders, bipolardisorders and substance abuse or dependence within the past six months)if the MDD diagnosis was primary. MDD severity, as measured by theHamilton Depression Rating Scale (Ham-D)-17 item version, had to bemoderate (Ham-D>16), and participants with very severe MDD (Ham-D>27)were excluded and referred for treatment due to safety concerns ofparticipating in an unproven antidepressant study. Participants with ahistory of treatment non-response (2+ failures of an adequate trial of astandard antidepressant medication) or chronic, non-episodic MDD wereexcluded from participation, as were participants with visual or motorimpairment that would interfere with performance on the computerizedexercise. Thirty potential participants were screened for the study; sixdid not meet inclusion/exclusion criteria and three were eligible butdecided not to participate.

The Program for the Protection of Human Subjects at Mount Sinai approvedthe protocol and study procedures, which were conducted in accordancewith the Declaration of Helsinki. After screening, eligible participantswere informed about the study procedures and signed informed consent.Participants were informed that the study would evaluate the effects oftwo different memory training exercises on memory and MDD symptoms. Thiswas not presented as an intervention study, and participants were notinformed of the differences between the cognitive-emotional and controltraining paradigms, thereby maintaining the study blind and minimizingplacebo effects. After completing the study, participants weredebriefed, including a description of the study blinding involved andthe rationale. Participants were reimbursed for each study sessioncompleted to compensate for time and travel expenses.

E-1-1-2 Procedure.

The study comprised 11 sessions. In the first, the SCID and Ham-D-17were administered. A baseline session was then conducted to assessattention and working memory, cognitive processing biases and MDDsymptoms. To assess attention span and working memory, a composite scorewas calculated as the mean scaled score from the Digit-Span Forward(DSF), Digit-Span Backward (DSB) and Letter-Number Sequencing (LNS)subtests of the Wechsler Adult Intelligence Scale-3^(rd) Edition(Wechsler D (1997): Wechsler Adult Intelligence Scale—Third Edition. SanAntonio: The Psychological Corporation). Measures ofcognitive-processing biases included assessments of rumination(Ruminative Responses Scale (RRS) (Treynor et al., Cognitive Ther Res27: 247-259 (2003)) and negative bias in short-term memory forself-descriptors (Self-Referential Information Processing task;SRIP)(Murray et al., Memory 7: 175-196 (1999)). The SRIP involvespresenting self-descriptors (positive and negative) and asking theparticipant to indicate whether the word “sounds like me”. Participantsare later asked to recall as many of the words as they can remember. Theproportion of negative self-descriptors accurately recalled is used asan index of the negative bias in short-term memory in MDD. MDD symptomswere assessed using the Ham-D-17.

Participants were randomly assigned to the cognitive-emotional orcontrol training groups by a research coordinator using a pre-determinedsequence for group assignment, generated by an independentbiostatistician. Participants completed eight training sessions over 4weeks (30-45 minutes each, twice per week). Weekly Ham-D assessmentswere conducted by PhD or MD-level clinicians who were blind to groupassignment. Ham-D raters were extensively trained to administer theassessment and demonstrated ICC>0.8 on two separate training interviews.An outcome session was administered within 1 week of completing thetraining sessions, at which time the baseline assessment was repeated.

E-1-1-3 Cognitive Training Exercises.

The cognitive-emotional training exercise is a combination of emotionidentification and working memory tasks: the Emotional Faces Memory Task(EFMT). In this task, participants identify the emotions they observe ona series of pictures of faces presented on a computer screen, andremember the sequence of emotions. Using an N-back working memorytraining paradigm, for each face observed participants indicate whetherthe emotion is the same as the emotion N faces back. The N level variesby block depending on performance; N can decrease or increase acrossblocks. Participants complete 15 blocks per session. Session 1 beginswith N=1 and the N for subsequent sessions is determined by performanceat the prior session. The task hones in on the participant's abilitylevel while consistently challenging them. In a single, non-progressivesession in healthy volunteers, this task simultaneously activated DLPFCand amygdala (Neta et al., NeuroImage 56: 1685-1692 (2011)).Progressively challenging n-back working memory tasks have been shown toimprove working memory performance (Jaeggi et al, Proc Natl Acad Sci USA105: 6829-6833 (2008)) but a progressively challenging working memoryparadigm with emotional stimuli has not yet been reported. The controltraining (CT) task is an active comparator consisting of an identicalcognitive-training paradigm to EFMT except the stimuli were neutralshapes (circle, square, etc.), thereby isolating the simultaneousactivation of amygdala and DLPFC to the EFMT group.

E-1-2 Study Design.

The study was designed as a double-blind, randomized, controlled,proof-of-concept trial to determine the effects of a regimen of eightcognitive-emotional training sessions on cognitive-processing biases,working memory and MDD symptoms in MDD participants. As outcomemeasures, changes in rumination (RRS), short-term memory for positiveand negative self-descriptors (SRIP), attention and working memory (DSF,DSB and LNS) and MDD symptoms (Ham-D) were assessed before and after thetraining regimens.

E-1-3 Data Analytic Strategy.

The effect of EFMT vs. CT training on MDD symptoms was the primaryanalysis of interest in this proof-of-concept study. A repeated-measuresANOVA of Ham-D change, with group (EFMT v. CT) as the between-factor andtime (baseline v. outcome) as the within-factor was planned toinvestigate the effects on MDD symptoms. Secondary analyses aimed toevaluate changes in cognitive processing biases and working memory.Given the small sample sizes and resulting limited power to detectsignificant effects, this study planned exploratory analyses of thechange within-groups (EFMT or CT) over time, and to estimate effectsizes for the difference in change scores between groups, as theanalytic procedure. Effect sizes were of primary interest to begin todescribe the possible effects of the cognitive training intervention,and t-tests were conducted within-groups although the power to detectsignificant p-values (α<0.05) was limited. Effect sizes were interpretedas per Cohen 1988 (Cohen J: Statistical Power Analysis for theBehavioral Sciences, 2nd ed. Hillsdale, N.J.: Lawrence EarlbaumAssociates (1998)): “small”=0.2<d<0.3; “medium”=d=0.5; “large”=d<0.8.Between-groups analyses of the cognitive variables were not planned dueto limited power and the exploratory nature of the analyses.

E-1-4 Results.

Table 1 provides the demographic and clinical characteristics of thestudy sample. Eleven participants were assigned to EFMT and ten to CT.All twenty-one participants completed all 8 training sessions over 4weeks with no attrition. Performance on the task (mean N-level achievedat each session) improved over time in both groups. At week four theEFMT group achieved a mean N-level of 5.5 and the CT group 5.6.

TABLE 1 Demographic and Clinical Characteristics of the Study SampleEFMT CT Number of patients 11 10 Age (years) 36.33 (8.5)   39.5 (8.19)Gender 6 Female, 5 Male 5 Female, 5 Male Ethnicity 5 African-American 5African-American 4 Caucasian 5 Caucasian 2 Asian Baseline Depression21.55 (2.97) 19.80 (2.79) Severity (Ham-D-17) Duration of current MDD20.9 (6.4) 19.1 (7.5) episode (months) Number of previous MDD  1.9 (.65)1.84 (.49) episodes Axis I Comorbidities 27% Social Phobia 20% SocialPhobia (current) 18% Generalized 20% Generalized Anxiety Anxiety 18%PTSD 10% PTSD Note: Standard deviation in parenthesis.

FIG. 4A depicts a reduction in mean Ham-D scores between baseline andoutcome in the EFMT group from 21.55 to 10.91 that was significantlylarger than the reduction in the CT group from 19.80 to 14.10 (Group[EFMT v. CT]×Time [baseline v. outcome] ANOVA: F(1, 19)=5.605, p=0.029).At week 4, the difference in Ham-D scores between groups approachedsignificance, t(19)=1.91, p=0.07. Both groups showed main effects oftime in Ham-D reduction (EFMT: t(10)=8.86, p<0.001; CT: t(9)=3.27,p=0.01). The effect size for the difference between groups in change inMDD symptoms over time (ΔHam-D: EFMT=−10.64; CT=−5.7) was large: d=0.82.Six of the 11 EFMT participants, and one of the ten CT participants,achieved ≥50% reduction in Ham-D score between baseline and outcome,which is the standard for defining a “responder” in clinical MDD trials.

The EFMT group demonstrated a medium-size but non-significant reductionin rumination (RRS) scores from 28.45 to 25.45, t(10)=1.54, p=0.14,dΔ=−0.66. The CT group demonstrated a small, non-significant increasefrom 28.8 to 30.6, t(9)=0.88, p=0.39, dΔ=0.39. The effect size for thedifference between groups in rumination change over time wasmedium-sized: d=0.64. On the Self-Referential Information Processing(SRIP) task, the EFMT group showed a significant reduction in short-termmemory for negative self-referential information (proportion of negativeself-descriptors accurately recalled after a delay) from 0.1852 to0.1697, t(10)=2.23, p=0.037, dΔ=−0.79. The CT group showed a small,non-significant increase from 0.1845 to 0.1885, t(9)=0.63, p=0.535,dΔ=0.27 (see FIG. 4B). The effect size for the difference in changescores between groups was medium-sized: d=0.60.

Both groups demonstrated similar, small improvements in attention spanand working memory after training (DSF, DSB and LNS composite score).The EFMT group demonstrated an increase from 10.3 to 11.36 (t(10)=1.855,p=0.09, dΔ=0.31), the CT group demonstrated an increase from 10.8 to11.25 (t(9)=1.01, p=0.34, dΔ=0.20), and the composite scores were notsignificantly different between groups at baseline or at week 4.

E-1-5 Conclusion.

The differential effects of EFMT versus CT in this study indicate thatcognitive-emotional training can be an intervention strategy for MDD,targeting impaired cognitive control for emotional informationprocessing and the underlying neural network functioning abnormalities.These interventions can be feasible and relatively low-cost, eventuallydisseminated to a participant's home via computer. Such interventionscan serve as an augmentation strategy for traditional interventions suchas medications or cognitive-behavioral therapy. Additionally, thesetypes of interventions may be accessible for populations that cannotmake use of traditional interventions (pregnant females or medically illindividuals for whom antidepressant medications are not indicated, forexample).

Example 2. Clinical Trial

The objective of this trial is to investigate the effectiveness of thedisclosed computerized training paradigm to modify the negative bias inworking memory and whether improvement in this domain transfers to otherdomains of cognitive processing that are also impaired in depression(facial emotion recognition, self-referential information processing andattribution style).

As such, one specific aim of this trial is to measure the effectivenessof the Emotional Faces Memory Task in reducing depressive symptoms inmajor depressive disorder (MDD) participants compared to the placebocontrol task (PCT). It is believed that MDD participants undergoing sixweeks of EFMT training will demonstrate greater improvement ofdepressive symptoms than MDD participants undergoing the PCT.

Another specific aim of this trial is to measure the effects of EFMT onnegative affective biases in information-processing. It is believed thatEFMT training, compared to PCT, will result in reduced negativeaffective bias in information processing.

Another specific aim of this trial is to measure the neurocognitiveeffects of EMFT training. It is believed that both EFMT and PCT traininggroups will show improvement across neurocognitive domains.

Major depressive disorder (MDD) is a common, severe, chronic and oftenlife-threatening illness that affects approximately 17% of the generalpopulation. The impairment in physical and social functioning resultingfrom MDD can be as severe as other chronic medical illnesses. Despiteimportant advances in the treatment of depression, many patients withthis illness remain inadequately treated, often due to treatmentnoncompliance. It is estimated that only 60 to 70% of patients treatedwith an antidepressant respond to the initial trial of pharmacotherapy.As MDD continues to pose a significant public health problem, with highrates of morbidity and mortality, well-tolerated new interventions arenecessary.

Research has consistently documented that depressed individualsdemonstrate a negative affective bias such that they tend to biasperception and processing towards negative information as compared topositive or neutral information. This negative affective bias has beendocumented in several domains of perception and processing includingworking memory, emotional processing, self-referential informationprocessing and attributional style. Importantly, the presence of anegative affective bias across each of these domains of processing indepression may be due to shared underlying neural circuitry. Indeed, thebrain regions involved in each of these domains of perception andprocessing are all part of larger networks that have been implicated innormal emotion perception as well as the pathophysiology of depression.Recent research has been aimed at modifying various cognitive biases indepression and anxiety disorders through cognitive training, withpromising initial results.

E-2-1 Study Design.

E-2-2 Recruitment Methods.

Subjects are recruited through advertisements in local newspapers andwebsites such as craigslist and clinical connections. Participants arealso recruited through the ongoing, IRB approved, MAP recruitment andscreening protocol.

E-2-2-1 Inclusion and Exclusion Criteria.

Inclusion criteria are (i) primary, current axis I diagnosis of majordepressive disorder according to DSM-IV criteria and a Ham-D-17 scorebetween 16-27, (ii) age between 18 and 55, and (iii) an ability to giveinformed consent. As such, patients with a primary diagnosis of majordepressive disorder are admitted. Moreover, some patients also havecomorbid (secondary) affective disorder diagnoses such as posttraumaticstress disorder, social phobia, generalized anxiety disorder, specificphobias, and borderline personality disorder and the disclosed trial andthe disclosed systems and methods is expected to improve symptoms(reduction of at least 50% in depression symptoms) of such patients aswell.

Exclusion criteria are any of (i) a history of drug or alcohol abuse ordependence (DSM-IV criteria) within 6 months, (ii) visual impairmentthat would affect the ability to observe the computerized presentationof faces or other images that induce induce amygdala activation, (iii)motor impairment that would affect the ability to provide a response byquickly pressing a button, (iv) lifetime history of bipolar spectrumdisorders or schizophrenia spectrum disorders, (v) primary, current AxisI diagnosis other than major depressive disorder, (vi) primary, currentAxis II personality disorder, (vii) currently attending acognitive-behavioral psychotherapy regimen, (viii) acute suicidal orhomicidal risk (evidenced by suicidal or homicidal attempt within 6months of screening), and (ix) pregnancy.

Enrolled participants can be currently taking medication but arestabilized on their medication regimens before enrolling in the study(i.e., no medication has been started within 8 weeks, stopped within 6weeks or titrated up or down within 4 weeks of study entry).Accordingly, if a patient's medication status must change during thecourse of the study, are discontinued from the study. No medications arediscontinued for the purpose of enrollment into the study.

Subjects exhibit no or only moderate alcohol use. Subjects with currentexcessive use of alcohol (>8 ounces/day for men and >6 ounces/day forwomen) are ineligible for participation, as such drug use could confoundthe results. The target recruitment for this study is eighty people.

E-2-2 Study Timelines.

E-2-2-1 Individual Subjects' Participation.

All participants require baseline behavioral assessment measures. Theyare then randomly assigned to either a training group or control group,and required to make 18 three-times-weekly appointments over 6 weeks.The estimated duration of an individual subject's participation is thatis last 10 weeks depending on scheduling flexibility for diagnostic,baseline and post measures. The approximate recruitment duration is fiveyears.

E-2-2-2 Study Endpoints.

This study ends once target recruitment goals have been met.

E-2-3 Procedures Involved.

A double-blind randomized design is used in which depressed subjects areassigned to undergo one of two procedures: the Emotional Faces MemoryTask (EFMT) training paradigm or a placebo control task (PCT) which is acomputer task designed to match the number of sessions attended andexposure to computerized stimuli. Subjects initially undergo a screeningand diagnostic evaluation to determine eligibility for participation.Upon meeting inclusion criteria, participants are assigned to either thetraining group or the control group, based on a predeterminedrandomization algorithm that includes medication status as a factor. Aninitial session to obtain baseline levels of depression symptoms(BDI-II), rumination (RRS), neuropsychological functioning (DS and LNS),verbal memory (HVLT), facial emotion recognition ability (EFRT),cognitive/affective processing biases (eStroop and Affective Go/No-Go(AGNG)), and outcome measures (CSQ, SRIP, and LOT-R) is then conducted.All participants attend 18 sessions during which they either receive thetraining paradigm or the placebo control task. After the 18 sessions,the baseline assessments are repeated.

E-2-4 Screening Interview (Approximately 1 Hour).

Subjects referred to the study or responding to advertisements for thestudy are educated about the protocol. Subjects interested inparticipating sign a consent form in order to proceed with a screeningand diagnostic interview. This interview includes collecting demographicinformation and a psychosocial battery including a diagnostic interview(SCID) and Hamilton Rating Scale for Depression (Ham-D-17) to confirmMDD diagnosis and to rule out exclusion criteria.

Individuals who are screened for the study and are found to have apreviously undiagnosed psychiatric disorder or medical condition aremade aware of the diagnosis/condition and are provided with referrals(either to their current primary care physician or to anotherappropriate referral) for treatment or further consultation if they sodesire.

E-2-5 Baseline Assessment (Approximately 2.5 Hours).

Participants attend a baseline assessment session at which time they areadministered a self-report assessment of depression symptoms (the BeckDepression Inventory-II (BDI-II), rumination (RRS), and an assessment ofneuropsychological functioning (Digit Span and Letter-Number Sequencing)and verbal memory (HVLT). At this session, participants are administeredsecondary measures, to attain a baseline. These include the EmotionFaces Recognition Task (EFRT), emotional Stroop (eStroop), AffectiveGo/No-go (AGNG), Cognitive Style Questionnaire (CSQ), theSelf-Referential Information Processing (SRIP) task, and an Optimismquestionnaire (LOT-R). At this session, to assess the acceptability ofcognitive training as a potential intervention strategy for depression,participants will be asked to rate the acceptability on a singleLikert-scale item.

E-2-6 Training Sessions or Control Group Sessions (35 Minutes Each).

The training condition is three-times-weekly for 6 weeks (18 sessionstotal). Subjects in the training condition complete the EFMT task forthe purposes of increasing their ability to accurately identify andremember facial emotions. For the control condition, the control groupattend three-times-weekly sessions for 6 weeks, at which they completethe Placebo Control Task (PCT), and an adaptive n-back working memoryassessment using shapes as the stimuli. This is to control variousconfounding factors that could potentially impact the outcome variables,such as improvement in working memory due to training, the number ofsessions attended, interactions with study staff and placebo effects dueto expectations for improvement based on attending a cognitive training.

E-2-7 Mid-Study Assessment (Week 3; Approximately 45 Minutes).

At the mid-study assessment session, to take place at the end of theparticipants' third week of training, participants complete the RRS,eStroop, EFRT and AGNG to monitor changes in cognitive and affectiveprocessing that might precede changes in mood symptoms.

E-2-8 Outcome Assessment (Approximately 2.5 Hours).

At the outcome assessment session, participants complete the BDI-II,RRS, DS, LNS, HVLT, EFRT, eStroop, AGNG, CSQ, SRIP, and LOT-R. At thissession, participants also complete a questionnaire to rate 1) theacceptability of cognitive training for depression as a possibleintervention strategy; 2) the perceived helpfulness of the cognitivetraining regimen they participated in. Ratings are provided on twolikert-scale items, respectively.

E-2-9 Follow-Up Assessments (Approximately 0.5 Hours Each).

Study completers (participants who complete at least 15 trainingsessions and the baseline and outcome sessions) are interviewed at2-weeks, 4-weeks, 6-weeks, 8-weeks, 16-weeks and 24-weeks after theOutcome Assessment to collect pilot data on the course of MDD symptomsafter the EFMT and PCT regimens. Follow-up assessments will involve theHam-D interview administered by trained study clinicians.

E-2-10 Suicidality Assessments.

Upon study enrollment, participants discuss with a study investigatorthe plan for monitoring and handling emergent suicidality during studyparticipation. Participants are provided with the PI's direct contactnumber (including cell phone number provided on the consent form) andencouraged to call if suicidal thinking emerges or worsens. Theparticipant also identifies the emergency room closest to their home,and is instructed to call 911 or 1-800-LIFE-NET or go to the nearestemergency room in the event that they feel they are in danger of harmingthemselves and they are unable to contact the PI (or if they feel it isan emergency that cannot wait for contacting the PI).

The baseline assessment and the outcome assessment sessions also includean assessment of suicidal ideation. Moreover, every week throughout thestudy patients meet briefly with a study clinician (a licensed clinicalprofessional; MD Psychiatrist or PhD Clinical Psychologist) to ask abouttheir mood and any suicidal ideation they have experienced since thelast session, using a standardized and validated assessment ofsuicidality (the Columbia Suicide Severity Rating Scale, C-SSRS) andclinician rated improvement/worsening scale (CGI) for study datacollection purposes.

In addition to the weekly depression and suicidality symptom assessmentconducted by the study investigators (including standardized ratingscales: Columbia Suicide Severity Rating Scale (CSSRS) and HamiltonDepression Rating Scale (Ham-D)), all patients are interviewed weekly bya NON-STUDY (not a study investigator, mentor or collaborator, as perthe K23 application), licensed clinician from within the Mood andAnxiety Disorders Program (MAP) at Mount Sinai. Licensed clinicians atMAP have extensive experience assessing and monitoring serious mood andanxiety disorder symptoms and suicidality. These interviews include anassessment of depression symptoms and the occurrence of passive oractive suicidal ideation/intent/plan/actions. Significant worsening ofsymptoms, or increased suicidal ideation, can be a common occurrence indepressed patients but still needs to be taken very seriously. In theevent that a patient exhibits significant suicidal ideation, and in thejudgment of the interviewer the patient is at risk of harmingthemselves, then: (i) the patient is escorted to a hospital emergencyroom for assessment for inpatient hospitalization, and (ii) the patientis withdrawn from the study to obtain necessary treatment. If thepatient is not hospitalized, and a treatment plan is not establishedthrough the emergency room, then (a) the patient is provided outpatienttreatment for three months free of charge. This free follow-up period isoffered to all subjects enrolled in MAP studies and can include:evaluation and ongoing treatment with a psychiatrist, includingprovision of a prescription that can be filled at the patient's localpharmacy; psychotherapy with a psychologist or social worker; or bothpharmacotherapy and psychotherapy if warranted. The free follow-upperiod is also be used by clinicians to advise the patient on findinglong-term care in his/her local community, according to theirinsurance/ability to pay. Clinicians suggest options for long-termtreatment and make appropriate referrals. If the patient is alreadyunder the care of a mental health treatment provider, and if the patientprefers not to pursue three months of free treatment through MAP, theywill be referred back to their treatment provider after consultationwith the provider regarding the reasons for study discontinuation andthe investigators' concerns about the patient's safety. All studypatients sign a waiver at study enrollment that provides the contactinformation for current treatment providers and grants studyinvestigators the right to contact current treatment providers in thecase of emergency or risk of harm.

E-2-11 Data Analytic Strategy.

Aim 1: Measure the effectiveness of EFMT in reducing depressive symptomsin MDD participants compared to PCT. Hypothesis 1: MDD participantsundergoing six weeks of EFMT training will demonstrate greaterimprovement of depressive symptoms than MDD participants undergoing thePCT. Analytic Strategy: intent-to-treat analyses is conducted, includingall participants that complete at least 1 week of training. The primaryanalysis for this proof-of-concept study is based on a Bayesian approachwith emphasis on estimating the posterior probability distribution ofthe mean between-group difference in Ham-D change from baseline to finalassessment. This flexible approach allows estimation of the probabilitythat EFMT is superior to PCT in reducing Ham-D scores by any amount(e.g., more than 0, more than 2, etc.), in addition to providing a testof the corresponding frequentist null hypothesis of no difference. Thisapproach assumes a non-informative diffuse normal prior probabilitydistribution for the difference in Ham-D scores between groups,reflecting a null hypothesis of no difference (e.g., a N(0,25) prior).This prior distribution is updated by incorporating observed results,and the resulting posterior distribution used to compute the probabilitythat EFMT is superior to PCT by any specified amount. In addition to theBayesian analysis, a more traditional intent-to-treat analysis ofcovariance (ANCOVA) is conducted to determine the adjusted (for baselineand number of training sessions) difference in Ham-D scores between EFMTand PCT groups. In this ANCOVA the factor is group (EFMT or PCT), finalHam-D score is the dependent variable, baseline Ham-D score and thenumber of training sessions completed are covariates.

E-2-12 Aim 2.

Measure the effects of EFMT on negative affective biases ininformation-processing. Hypothesis 2: EFMT training will result inreduced negative affective bias in information processing. AnalyticStrategy: ANCOVAs are conducted to evaluate changes incognitive/affective processing assessments between EFMT and PCT groups.In separate ANCOVA analyses for each measure, the factor will be group(EFMT or PCT) and final score (RRS, eStroop, AGNG, EFRT, LOT-R, SRIP orCSQ) is the dependent variable, with baseline score and number oftraining sessions completed as covariates.

E-2-13 Aim 3.

Measure the neurocognitive effects of EMFT training. Hypothesis 3: EFMTand PCT groups will show similar improvement in neurocognition. AnalyticStrategy: ANCOVAs is conducted for the effect of training on (1)attention and memory span (DSF), (2) working memory (DSB and LNScomposite score) and (3) verbal memory (HVLT). Participants who fail toreach a mean performance level of 2.5 on the cognitive training task forat least one week of training (during any week of the study) areexcluded from the final data analysis.

E-2-14 Intermediate Results.

Table 2 provides intermediate results for a 23 patient group in whichthere were 12 patients in group A and 11 in group B. The goal of thisblinded study data is to show that participants in one of the studygroups are meeting clinical response criteria (reduction of at least 50%in depression symptoms) much more frequently than in the other group.This indicates that the intervention provided for this group is moreeffective in reducing MDD symptoms. It is expected that, when the dataare unblinded, that this group is the active cognitive-emotionaltraining group. To date, there have been no adverse side effects orother adverse events that have occurred as a result of the clinicaltrial procedures. Numerous patients have shown significant improvementas a result of their participation in the study, presumably as a resultof the cognitive-emotional training intervention, leading to ourexpectation that the intervention will be found to be effective when thefinal data are analyzed. In Table 2, the “Baseline” and “Outcome”numbers are the total score on the depression rating scale used in thestudy (the Hamilton depression rating scale 17-item version (HAM-D-17)).The two values for each patient (“Baseline” and “Outcome”) represent thebaseline (study beginning) and outcome (study endpoint); the changescore is provided as outcome minus baseline; and percent change ischange score divided by baseline score (multiplied by 100).

TABLE 2 Baseline Outcome Change % Change Group A 1 20 12 −8 −40 2 18 14−4 −22.22 3 18 18 0 0 4 22 18 −4 −18.18 5 17 16 −1 −5.88 6 17 17 0 0 723 25 2 8.7 8 22 25 3 13.64 9 22 19 −3 −13.64 10  16 10 −6 −37.5 11  167 −9 −56.25 12  19 15 −4 −21.05 A_mean 19.16667 16.33333 −2.83333−16.0317 Group B 1 18 5 −13 −72.22 2 17 4 −13 −76.47 3 20 10 −10 −50 419 10 −9 −47.37 5 16 13 −3 −18.75 6 21 10 −11 −52.38 7 19 12 −7 −36.84 826 19 −7 −26.92 9 21 17 −4 −19.05 10  17 8 −9 −52.94 11  16 11 −5 −31.25B_mean 19.09091 10.81818 −8.27273 −44.0173

One of 12 patients in group A “responded” (had at least 50% reduction insymptoms); whereas 5 of 11 in group B responded. Although formalstatistical analyses has not been done at this time (not until the datais unblinded for the interim analysis) the data indicates that there isa statistically significant difference between the groups.

The terminology used in the description of the invention herein is forthe purpose of describing particular implementations only and is notintended to be limiting of the invention. As used in the description ofthe invention and the appended claims, the singular forms “a,” “an,” and“the” are intended to include the plural forms as well, unless thecontext clearly indicates otherwise. It will also be understood that theterm “and/or” as used herein refers to and encompasses any and allpossible combinations of one or more of the associated listed items. Itwill be further understood that the terms “comprises” and/or“comprising,” when used in this specification, specify the presence ofstated features, steps, operations, elements, and/or components, but donot preclude the presence or addition of one or more other features,steps, operations, elements, components, and/or groups thereof.

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes.

The foregoing description, for purpose of explanation, has beendescribed with reference to specific implementations. However, theillustrative discussions above are not intended to be exhaustive or tolimit the invention to the precise forms disclosed. Many modificationsand variations are possible in view of the above teachings. Theimplementations described herein were chosen and described in order tobest explain the principles of the invention and its practicalapplications, to thereby enable others skilled in the art to bestutilize the invention and various implementations with variousmodifications as are suited to the particular use contemplated.

What is claimed is:
 1. A computing system, comprising: one or moreprocessors; memory; and one or more programs, wherein the one or moreprograms are stored in the memory and are configured to be executed bythe one or more processors to treat a subject in need of treatment of apsychiatric disorder, the one or more programs including instructionsfor: conducting a therapy session, the therapy session comprising: i)sequentially displaying each respective expression image in a pluralityof expression images, the plurality of expression images comprising aplurality of subsets of expression images, wherein each expression imagein the plurality of expression images is (a) independently associatedwith a respective expression in a set of expressions, (b) engineered todisplay or exhibits a predetermined intensity of the respectiveexpression on an intensity scale that ranges from a first intensitylevel to a second intensity level of the respective expression and (c)configured to induce human amygdala activation, ii) responsive tocompletion of each respective expression image subset within theplurality of expression images, receiving a response from the subject toa query as to whether the first and the last expression image in therespective expression image subset exhibits the same emotion, andwherein each respective expression image subset within the plurality ofexpression images consists of N expression images, wherein N is apredetermined integer, iii) determining a score for each respectiveexpression image subset within the plurality of expression images basedat least in part upon the response to the query for the respectiveexpression image subset, and iv) resetting the value of N to a newpositive integer value based at least in part on the plurality ofscores.
 2. The computing system of claim 1, wherein the i) sequentiallydisplaying, ii) receiving, iii) determining, and iv) resetting arerepeated a plurality of times in the therapy session.
 3. The computingsystem of claim 1 wherein the predetermined intensity of the respectiveexpression on the intensity scale of respective images of a first subsetof expression images in the plurality of expression images is less thanthe predetermined intensity of the respective expression on theintensity scale of respective images in the plurality of expressionimages of a second subset of expression images in the therapy session,wherein the second subset is displayed after the first subset.
 4. Thecomputing system of claim 1, wherein the set of expressions compriseshappy, worried, angry and sad.
 5. The computing system of claim 1,further comprising prescribing a treatment regimen to the subject forthe psychiatric disorder and wherein the treatment regimen comprises afrequency of conducting the therapy session and an absolute number oftimes to conduct the therapy session.
 6. The computing system of claim1, further comprising prescribing a treatment regimen to the subject forthe psychiatric disorder and wherein the treatment regimen comprises theuse of a pharmaceutical composition.
 7. The computing system of claim 6,wherein the psychiatric disorder is MDD and the pharmaceuticalcomposition is a selective serotonin reuptake inhibitor (SSRI), aserotonin norepinephrine reuptake inhibitor (SNRT), a cognitiveenhancer, ketamine or ketamine derivative, an atypical antipsychotic, abenzodiazepine, bupropion, amotrigine, lithium, a monoamine oxidaseinhibitor, a tricyclic antidepressant, valproic acid, nefazodone,trazodone, pramipexole or combinations thereof; or wherein thepsychiatric disorder is post traumatic stress disorder (PTSD) and thepharmaceutical composition is an SSRI, an SNRT, a cognitive enhancer,ketamine or ketamine derivative, or combinations thereof; or wherein thepsychiatric disorder is general anxiety disorder and the pharmaceuticalcomposition is an SSRI, an SNRT, a cognitive enhancer or combinationsthereof; or wherein the psychiatric disorder is social phobia and thepharmaceutical composition is an SSRI, an SNRI, a cognitive enhancer orcombinations thereof; or wherein the psychiatric disorder is obsessivecompulsive disorder and the pharmaceutical composition is an SSRI, acognitive enhancer or combinations thereof; or wherein the psychiatricdisorder is borderline personality disorder and the pharmaceuticalcomposition is an SSRI, an SNRI, ketamine or ketamine derivative, acognitive enhancer or combinations thereof.
 8. The computing system ofclaim 1, wherein the psychiatric disorder is an affective disorder (AD).9. The computing system of claim 8, wherein the AD is major depressivedisorder (MDD), post traumatic stress disorder (PTSD), general anxietydisorder, social phobia, obsessive compulsive disorder, treatmentresistant depression, or borderline personality disorder.
 10. Thecomputing system of claim 1, further comprising prescribing a treatmentregimen to the subject for the psychiatric disorder and wherein thetreatment regimen comprises a frequency of conducting the therapysession, an absolute number of times to conduct the therapy session, andthe use of a brain stimulation intervention.
 11. The computing system ofclaim 1, wherein sequentially displaying each respective expressionimage in a plurality of expression images includes sequentiallydisplaying each respective expression image in a plurality of expressionimages for a predetermined amount of time for a predetermined amount oftime and wherein the predetermined amount of time is less than 10seconds.
 12. The computing system of claim 1, wherein the predeterminedamount of time is between 0.2 seconds and 10 seconds.
 13. The computingsystem of claim 1, further comprising prescribing a treatment regimen tothe subject for the psychiatric disorder and wherein the prescribingcomprises communicating the score to a remote server for evaluation by aprescribing clinician.
 14. The computing system of claim 1, wherein thesequentially displaying comprises retrieving the first subset of theplurality of expression images from a database that stores the pluralityof expression images, wherein the database stores, for each respectiveexpression image in the plurality of expression images, the emotionassociated with the expression image.
 15. The computing system of claim1, wherein the respective expression image subsets are overlapping, andwherein each subset overlaps by N−1 images with another respective imagesubset.
 16. The computing system of claim 1, wherein the plurality ofscores is determined as the total number of correct responses from thesubject to the query as to whether the first and last expression in therespective expression image subset is the same.
 17. The computing systemof claim 16, wherein the resetting of N is based at least in part on thepercentage of correct responses from the subject to the query ascompared to the total number of response.
 18. The computing system ofclaim 17, wherein N is reset to N+1 when the percentage of correctresponses is greater than a first threshold percentage, N is reset toN−1 when the percentage of correct responses is less than a secondthreshold percentage, and N does not reset when the percentage ofcorrect responses is between the first and second threshold percentage.19. The computing system of claim 1, wherein the one or more programsinclude instructions for i) conducting an initial assessment of thesubject prior to the conducting the therapy to select the therapysession from among a plurality of therapy session treatment protocols;ii) conducting an assessment of the cognitive function or emotionalfunction of the subject after conducting the therapy session, whereinthe assessment is used as the basis, at least in part, for theprescribing a treatment regimen to the subject; or iii) providing thesubject with a performance evaluation based at least in part on theplurality of scores of a plurality of therapy sessions.
 20. Thecomputing system of claim 19, wherein the one or more programs includeinstructions for providing the subject with a performance evaluationbased at least in part on the plurality of scores.
 21. The computingsystem of claim 1, wherein at least one expression image in theplurality of expression images is not a facial expression.
 22. Thecomputing system of claim 1, wherein at least one expression image inthe plurality of expression images is a facial expression.
 23. Thecomputing system of claim 1, wherein the predetermined intensity of therespective expression on the intensity scale of respective displayedexpression images increases from the first intensity level to the secondintensity level across the therapy session, wherein the first intensitylevel is less than the second intensity level.
 24. A non-transitorycomputer readable storage medium storing one or more programs configuredfor execution by a computing device having one or more processors andmemory, the one or more programs comprising instructions for: conductinga session comprising: i) sequentially displaying each respectiveexpression image in a plurality of expression images, the plurality ofexpression images comprising a plurality of subsets of expressionimages, wherein each expression image in the plurality of expressionimages is (i) independently associated with a respective expression in aset of expressions, (ii) engineered to display or exhibit apredetermined intensity of the respective expression on an intensityscale that ranges from a first intensity level to a second intensitylevel of the respective expression and (c) configured to induce humanamygdala activation, ii) responsive to completion of each respectiveexpression image subset within the plurality of expression images,receiving a response from a subject to a query as to whether the firstand the last expression image in the respective expression image subsetexhibits the same emotion, and wherein each respective expression imagesubset within the plurality of expression images consists of Nexpression images, wherein N is a predetermined integer, iii)determining a score for each respective expression image subset withinthe plurality of expression images based at least in part upon theresponse to the query for the respective expression image subset, andiv) resetting the value of N to a new positive integer value based atleast in part on the plurality of scores.
 25. A method comprising:conducting a session comprising sequentially displaying each respectiveexpression image in a plurality of expression images, the plurality ofexpression images comprising a plurality of subsets of expressionimages, wherein each expression image in the plurality of expressionimages is (i) independently associated with a respective expression in aset of expressions, (ii) engineered to display or exhibits apredetermined intensity of the respective expression on an intensityscale that ranges from a first intensity level to a second intensitylevel of the respective expression and (iii) configured to induce humanamygdala activation, responsive to completion of each respectiveexpression image subset within the plurality of expression images,receiving a response from a subject to a query as to whether the firstand the last expression image in the respective expression image subsetexhibits the same emotion, and wherein each respective expression imagesubset within the plurality of expression images consists of Nexpression images, wherein N is a predetermined integer, determining ascore for each respective expression image subset within the pluralityof expression images based at least in part upon the response to thequery for the respective expression image subset, and resetting thevalue of N to a new positive integer value based at least in part on theplurality of scores.
 26. The method of claim 25, wherein the i)sequentially displaying, ii) receiving, iii) determining, and iv)resetting are repeated a plurality of times in the session.
 27. Themethod of claim 25, wherein the predetermined intensity of therespective expression on the intensity scale of respective images of afirst subset of expression images in the plurality of expression imagesis less than the predetermined intensity of the respective expression onthe intensity scale of respective images in the plurality of expressionimages of a second subset of expression images in the session, whereinthe second subset is displayed after the first subset.
 28. The method ofclaim 25, wherein the set of expressions comprises happy, worried, angryand sad.
 29. The method of claim 25, further comprising prescribing atreatment regimen to the subject for a psychiatric disorder and whereinthe treatment regimen comprises a frequency of conducting the sessionand an absolute number of times to conduct the session.
 30. The methodof claim 25, further comprising prescribing a treatment regimen to thesubject for a psychiatric disorder and wherein the treatment regimencomprises the use of a pharmaceutical composition.
 31. The method ofclaim 30, wherein the psychiatric disorder is an affective disorder(AD).
 32. The method of claim 31, wherein the AD is major depressivedisorder (MDD), post traumatic stress disorder (PTSD), general anxietydisorder, social phobia, obsessive compulsive disorder, treatmentresistant depression, or borderline personality disorder.
 33. The methodof claim 32, wherein the psychiatric disorder is MDD and thepharmaceutical composition is a selective serotonin reuptake inhibitor(SSRI), a serotonin norepinephrine reuptake inhibitor (SNRT), acognitive enhancer, ketamine or ketamine derivative, an atypicalantipsychotic, a benzodiazepine, bupropion, amotrigine, lithium, amonoamine oxidase inhibitor, a tricyclic antidepressant, valproic acid,nefazodone, trazodone, pramipexole or combinations thereof; or whereinthe psychiatric disorder is post traumatic stress disorder (PTSD) andthe pharmaceutical composition is an SSRI, an SNRT, a cognitiveenhancer, ketamine or ketamine derivative, or combinations thereof; orwherein the psychiatric disorder is general anxiety disorder and thepharmaceutical composition is an SSRI, an SNRT, a cognitive enhancer orcombinations thereof; or wherein the psychiatric disorder is socialphobia and the pharmaceutical composition is an SSRI, an SNRI, acognitive enhancer or combinations thereof; or wherein the psychiatricdisorder is obsessive compulsive disorder and the pharmaceuticalcomposition is an SSRI, a cognitive enhancer or combinations thereof; orwherein the psychiatric disorder is borderline personality disorder andthe pharmaceutical composition is an SSRI, an SNRI, ketamine or ketaminederivative, a cognitive enhancer or combinations thereof.
 34. The methodof claim 25, further comprising prescribing a treatment regimen to thesubject for a disorder and wherein the treatment regimen comprises afrequency of conducting the therapy session, an absolute number of timesto conduct the therapy session, and the use of a brain stimulationintervention.
 35. The method of claim 25, wherein sequentiallydisplaying each respective expression image in a plurality of expressionimages includes sequentially displaying each respective expression imagein a plurality of expression images for a predetermined amount of timefor a predetermined amount of time and wherein the predetermined amountof time is less than 10 seconds.
 36. The method of claim 35, wherein thepredetermined amount of time is between 0.2 seconds and 10 seconds. 37.The method of claim 25, further comprising prescribing a treatmentregimen to the subject for the psychiatric disorder and wherein theprescribing comprises communicating the score to a remote server forevaluation by a prescribing clinician.
 38. The method of claim 25,wherein the sequentially displaying comprises retrieving the firstsubset of the plurality of expression images from a database that storesthe plurality of expression images, wherein the database stores, foreach respective expression image in the plurality of expression images,the emotion associated with the expression image.
 39. The method ofclaim 25, wherein the respective expression image subsets areoverlapping, and wherein each subset overlaps by N−1 images with anotherrespective image subset.
 40. The method of claim 25 wherein theplurality of scores is determined as the total number of correctresponses from the subject to the query as to whether the first and lastexpression in the respective expression image subset is the same. 41.The method of claim 40, wherein the resetting of N is based at least inpart on the percentage of correct responses from the subject to thequery as compared to the total number of response.
 42. The method ofclaim 41, wherein N is reset to N+1 when the percentage of correctresponses is greater than a first threshold percentage, N is reset toN−1 when the percentage of correct responses is less than a secondthreshold percentage, and N does not reset when the percentage ofcorrect responses is between the first and second threshold percentage.43. The method of claim 25, wherein the one or more programs includeinstructions for i) conducting an initial assessment of the subjectprior to the conducting the session to select the session from among aplurality of session protocols; ii) conducting an assessment of thecognitive function or emotional function of the subject after conductingthe session, wherein the assessment is used as the basis, at least inpart, for the prescribing a treatment regimen to the subject; or iii)providing the subject with a performance evaluation based at least inpart on the plurality of scores of a plurality of sessions.
 44. Themethod of claim 43, wherein the one or more programs includeinstructions for providing the subject with a performance evaluationbased at least in part on the plurality of scores.
 45. The method ofclaim 25, wherein at least one expression image in the plurality ofexpression images is not a facial expression.
 46. The method of claim25, wherein at least one expression image in the plurality of expressionimages is a facial expression.
 47. The method of claim 25, wherein thepredetermined intensity of the respective expression on the intensityscale of respective displayed expression images increases from the firstintensity level to the second intensity level across the session,wherein the first intensity level is less than the second intensitylevel.
 48. A method for treatment of a psychiatric disorder of a subjectcomprising: i) sequentially showing each respective expression image ina plurality of expression images for a predetermined amount of time, theplurality of expression images comprising a plurality of subsets ofexpression images, wherein each expression image in the plurality ofexpression images is (a) independently associated with a respectiveexpression in a set of expressions, (b) engineered to display or exhibita predetermined intensity of the respective expression on an intensityscale that ranges from a first intensity level to a second intensitylevel of the respective expression and (c) configured to induce humanamygdala activation; ii) responsive to completion of each respectiveexpression image subset within the plurality of expression images,receiving a response from the subject to a query as to whether the firstand the last expression image in the respective expression image subsetexhibits the same emotion, and wherein each respective expression imagesubset within the plurality of expression images consists of Nexpression images, wherein N is a predetermined integer; iii)determining a score for each respective expression image subset withinthe plurality of expression images based at least in part upon theresponse to the query for the respective expression image subset; andiv) communicating the score to a remote server for evaluation by aprescribing clinician.
 49. The method of claim 25, further comprisingprescribing a treatment regimen to the subject for the psychiatricdisorder and wherein the treatment regimen comprises the use of apharmaceutical composition.
 50. The method of claim 25, wherein thepsychiatric disorder is an affective disorder (AD).
 51. The method ofclaim 50, wherein the AD is major depressive disorder (MDD), posttraumatic stress disorder (PTSD), general anxiety disorder, socialphobia, obsessive compulsive disorder, treatment resistant depression,or borderline personality disorder.
 52. The method of claim 48, furthercomprising prescribing a treatment regimen to the subject for thepsychiatric disorder and wherein the treatment regimen comprises afrequency of conducting the session and an absolute number of times toconduct the session.
 53. The method of claim 48, wherein the i)sequentially showing, ii) receiving, iii) determining, and iv) resettingare repeated a plurality of times in the session.
 54. The method ofclaim 48, wherein the predetermined intensity of the respectiveexpression on the intensity scale of respective images of a first subsetof expression images in the plurality of expression images is less thanthe predetermined intensity of the respective expression on theintensity scale of respective images in the plurality of expressionimages of a second subset of expression images in the session, whereinthe second subset is displayed after the first subset.
 55. The method ofclaim 48, wherein the set of expressions comprises happy, worried, angryand sad.
 56. The method of claim 51, wherein the psychiatric disorder isMDD and the pharmaceutical composition is a selective serotonin reuptakeinhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRT),a cognitive enhancer, ketamine or ketamine derivative, an atypicalantipsychotic, a benzodiazepine, bupropion, amotrigine, lithium, amonoamine oxidase inhibitor, a tricyclic antidepressant, valproic acid,nefazodone, trazodone, pramipexole or combinations thereof; or whereinthe psychiatric disorder is post traumatic stress disorder (PTSD) andthe pharmaceutical composition is an SSRI, an SNRI, a cognitiveenhancer, ketamine or ketamine derivative, or combinations thereof; orwherein the psychiatric disorder is general anxiety disorder and thepharmaceutical composition is an SSRI, an SNRI, a cognitive enhancer orcombinations thereof; or wherein the psychiatric disorder is socialphobia and the pharmaceutical composition is an SSRI, an SNRI, acognitive enhancer or combinations thereof; or wherein the psychiatricdisorder is obsessive compulsive disorder and the pharmaceuticalcomposition is an SSRI, a cognitive enhancer or combinations thereof; orwherein the psychiatric disorder is borderline personality disorder andthe pharmaceutical composition is an SSRI, an SNRI, ketamine or ketaminederivative, a cognitive enhancer or combinations thereof.
 57. The methodof claim 48, further comprising prescribing a treatment regimen to thesubject for the psychiatric disorder and wherein the treatment regimencomprises a frequency of conducting the therapy session, an absolutenumber of times to conduct the therapy session, and the use of a brainstimulation intervention.
 58. The method of claim 48, whereinsequentially showing each respective expression image in a plurality ofexpression images includes sequentially showing each respectiveexpression image in a plurality of expression images for a predeterminedamount of time for a predetermined amount of time and wherein thepredetermined amount of time is less than 10 seconds.
 59. The method ofclaim 48, wherein the predetermined amount of time is between 0.2seconds and 10 seconds.
 60. The method of claim 48, further comprisingprescribing a treatment regimen to the subject for the psychiatricdisorder and wherein the prescribing comprises communicating the scoreto a remote server for evaluation by a prescribing clinician.
 61. Themethod of claim 48, wherein the sequentially showing comprisesretrieving the first subset of the plurality of expression images from adatabase that stores the plurality of expression images, wherein thedatabase stores, for each respective expression image in the pluralityof expression images, the emotion associated with the expression image.62. The method of claim 48, wherein the respective expression imagesubsets are overlapping, and wherein each subset overlaps by N−1 imageswith another respective image subset.
 63. The method of claim 48 whereinthe plurality of scores is determined as the total number of correctresponses from the subject to the query as to whether the first and lastexpression in the respective expression image subset is the same. 64.The method of claim 63, wherein the resetting of N is based at least inpart on the percentage of correct responses from the subject to thequery as compared to the total number of response.
 65. The method ofclaim 64, wherein N is reset to N+1 when the percentage of correctresponses is greater than a first threshold percentage, N is reset toN−1 when the percentage of correct responses is less than a secondthreshold percentage, and N does not reset when the percentage ofcorrect responses is between the first and second threshold percentage.66. The method of claim 48, wherein the one or more programs includeinstructions for i) conducting an initial assessment of the subjectprior to the conducting the session to select the session from among aplurality of session protocols; ii) conducting an assessment of thecognitive function or emotional function of the subject after conductingthe session, wherein the assessment is used as the basis, at least inpart, for the prescribing a treatment regimen to the subject; or iii)providing the subject with a performance evaluation based at least inpart on the plurality of scores of a plurality of sessions.
 67. Themethod of claim 66, wherein the one or more programs includeinstructions for providing the subject with a performance evaluationbased at least in part on the plurality of scores.
 68. The method ofclaim 48, wherein at least one expression image in the plurality ofexpression images is not a facial expression.
 69. The method of claim48, wherein at least one expression image in the plurality of expressionimages is a facial expression.
 70. The method of claim 48 wherein thepredetermined intensity of the respective expression on the intensityscale of respective displayed expression images increases from the firstintensity level to the second intensity level across the session,wherein the first intensity level is less than the second intensitylevel.